Axial Connectivity of the Lung Microbiome: A Review of Interorgan Crosstalk

The classic organ-centric model of human physiology is rapidly giving way to a unified approach embracing the human body as an integrated network of bidirectional interorgan communication. The human microbiome serves as a fundamental mediator of this shift, regulating immune homeostasis, barrier integrity and metabolic signaling across organs. While the lung maintains a characteristic low-biomass microbiome in dynamic equilibrium, any disruption primes local and systemic immune responses contributing to disease. Beyond the well-described gut-lung axis, crosstalk between the lung and other distal organ systems is lesser recognized; however, increasingly acknowledged as a key under-appreciated contributor to respiratory disease including extrapulmonary complications. This review synthesizes current established evidence on axial connectivity of the lung microbiome across the gut, brain, skin, heart, kidney, and liver, and finds that such crosstalk is predominantly, though not exclusively gut-mediated. Direct lung-organ interactions are described for several axes; however, they remain preliminary. Across these lung-axial systems, common pathophysiological mechanisms emerge, including dysbiosis-induced depletion of microbial metabolites, immunomodulation, and barrier perturbations, all linking pulmonary disease with neuroinflammation, gastrointestinal deficits, and cardiac, renal, hepatic, and dermatological abnormalities. We assess how therapeutic modulation of interorgan systems offers promising avenues for improved risk stratification and novel therapeutics. Recognizing microbiome-mediated pulmonary-organ crosstalk represents an emerging conceptual framework in respiratory medicine, repositioning microbial communities as key modulators of extrapulmonary disease.